PGK1 epigenetically silences STING via DNMT1 and its knockdown synergizes with STING agonists in pancreatic cancer

  • Acta Pharmacol Sin. 2026 May 18. doi: 10.1038/s41401-026-01809-6.
Wan-Mei Liu  1  2 ,  Jia-Hui Xu  1  3 ,  Chun-Yong Ding  4  5 ,  Ao Zhang  6  7  8  9
Affiliations
  • 1. Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China.
  • 2. State Key Laboratory of Innovative Immunotherapy, Minhang District, Shanghai Jiao Tong University, Shanghai, 200240, China.
  • 3. Shanghai Artificial Intelligence Laboratory, Shanghai, 200433, China.
  • 4. Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China. [email protected].
  • 5. State Key Laboratory of Innovative Immunotherapy, Minhang District, Shanghai Jiao Tong University, Shanghai, 200240, China. [email protected].
  • 6. Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China. [email protected].
  • 7. State Key Laboratory of Innovative Immunotherapy, Minhang District, Shanghai Jiao Tong University, Shanghai, 200240, China. [email protected].
  • 8. Shanghai Artificial Intelligence Laboratory, Shanghai, 200433, China. [email protected].
  • 9. The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, 523808, China. [email protected].
PMID: 42144444 DOI: 10.1038/s41401-026-01809-6
Abstract

The highly immunosuppressive tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC) severely limits the efficacy of current immunotherapies. Identifying key molecular drivers of this immunosuppressive niche is therefore essential for developing new treatment strategies. In this study, through comprehensive bioinformatic analysis of PDAC clinical datasets and systematic experimental validation, we demonstrate that PGK1 is upregulated in PDAC and is associated with poor immune infiltration. Genetic knockdown of PGK1 upregulated STING expression, promoted the recruitment of antitumor immune cells into the tumor microenvironment, and significantly enhanced the in vivo efficacy of STING agonist treatment. Mechanistically, PGK1 stabilizes DNMT1 by blocking its ubiquitination-mediated degradation, which in turn promotes methylation of the STING promoter and suppresses its transcription. Our findings reveal a non-metabolic role of PGK1 in promoting an immunosuppressive microenvironment and propose a promising combination strategy targeting the PGK1-STING axis for the treatment of PDAC.

Keywords
DNMT1; PGK1; STING; antitumor effect; pancreatic adenocarcinoma.
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